A Slc5a6-Deficient Mouse Model Reveals Metabolically Driven Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention

Millie O. Fullerton; Lauren C. Phillips; Rachael E. Redgrave; Luke Spray; Vincent Haufroid; George Merces; Scott T. Kerridge; Gavin D. Richardson; Nathalie Mercier; Dominique Roland; Rebecca Crossley; Andrew D.H. Morgan; Joseph P. Dewulf; John Burn; Simon D. Bamforth; Helen M. Phillips

doi:10.1172/jci.insight.200381

A Slc5a6-Deficient Mouse Model Reveals Metabolically Driven Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention

Millie O. Fullerton,¹ Lauren C. Phillips,¹ Rachael E. Redgrave,¹ Luke Spray,² Vincent Haufroid,³ George Merces,⁴ Scott T. Kerridge,¹ Gavin D. Richardson,¹ Nathalie Mercier,⁵ Dominique Roland,⁶ Rebecca Crossley,¹ Andrew D.H. Morgan,¹ Joseph P. Dewulf,³ John Burn,¹ Simon D. Bamforth,¹ and Helen M. Phillips¹

Published June 2, 2026 - More info

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Abstract

The sodium-dependent multivitamin transporter, encoded by SLC5A6, mediates cellular uptake of biotin and pantothenic acid, essential cofactors for energy metabolism. We identified two families with SLC5A6 mutations presenting with early-onset dilated cardiomyopathy (DCM). To investigate the link between vitamin deficiency and cardiomyopathy, we generated a cardiac-specific SLC5A6 knockout (Slc5a6^cKO) mouse model and evaluated the impact of vitamin supplementation. Slc5a6^cKO mice developed progressive cardiac dysfunction, culminating in cardiac pathology and premature death at 26 weeks; earlier stages exhibited cardiomyocyte hypertrophy, fibrosis, impaired Coenzyme A synthesis, and metabolic imbalance, indicating progression toward cardiomyopathy. Cardiac magnetic resonance imaging and ECG confirmed progressive functional decline. Proteomic analysis revealed early mitochondrial metabolic disruption and extracellular matrix protein upregulation at 8 weeks, preceding overt cardiac dysfunction. Strikingly, vitamin supplementation from preconception onwards prevented the cardiac phenotype, preserving cardiac structure, function, morphology and survival. This paralleled the clinical outcome in one patient who received early vitamin treatment, compared to another who required a heart transplant without vitamin treatment. This study establishes a direct link between SLC5A6-mediated vitamin transport, mitochondrial function, and cardiac health. It highlights how vitamin deficiency contributes to cardiomyopathy pathogenesis and supports early vitamin supplementation as a potential therapeutic strategy for metabolic cardiomyopathies.

A Slc5a6-Deficient Mouse Model Reveals Metabolically Driven Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention

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A Slc5a6-Deficient Mouse Model Reveals Metabolically Driven Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention

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